Alzheimer's disease (AD) and other neurodegenerative diseases will have a global impact on health outcomes for people in the coming decades. Without a cure or preventative treatment, it is likely that the economic costs to the U.S. and other countries will be prohibitive, with estimates in the billions of dollars. Thus, understanding the pathobiology and physiology of the disease process will be integral for future therapeutic treatments. The presence of senile plaques and neurofibrillary tangles (NFTs) are hallmarks of Alzheimer's disease (AD). However, only NFTs have been shown to correlate with the severity of the associated dementia. NFTs have been shown to consist of aggregates of phosphorylated tau protein. Tau normally functions to stabilize microtubules in neuronal processes, but in diseased brain cells, tau becomes part of insoluble multi-protein NFT complexes as well as soluble pathogenic oligomers. The progression of the disease follows a well described path initially displaying NFT-associated neurodegeneration in a brain region called the entorhinal cortex followed by neurodegeneration in a downstream brain region called the hippocampus. Importantly, these brain regions are crucial for the formation of long term memories and are likely responsible for the memory loss observed in AD patients. This proposal will investigate the effect of pathogenic tau expression in medial entorhinal cortical neurons, which make their first synaptic connections with several different neuronal subtypes in the dentate gyrus of the hippocampus. The experimental design will involve adeno-associated viral vector transfection, optogenetics, and whole cell patch clamping to examine the effect of pathogenic tau on presynaptic function, postsynaptic function, and the propensity of tau to spread from the medial entorhinal cortex to specific cell types in the dentate gyrus. The specific cell types that we will investigate control hippocampal excitability and any observed changes in their function may help explain hippocampal hyperexcitability observed in AD patients. Thus, these studies will help identify synaptic and neuronal sites impaired by pathogenic tau during early stages of the disease. It is hoped that discoveries from these studies will provide targets for future therapeutic investigations.